Chemokine receptor antagonists and methods of use therefor

ABSTRACT

Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by the following structural formula:                    
     and physiologically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Chemoattractant cytokines or chemokines are a family of proinflammatorymediators that promote recruitment and activation of multiple lineagesof leukocytes and lymphocytes. They can be released by many kinds oftissue cells after activation. Continuous release of chemokines at sitesof inflammation mediates the ongoing migration of effector cells inchronic inflammation. The chemokines characterized to date are relatedin primary structure. They share four conserved cysteines, which formdisulfide bonds. Based upon this conserved cysteine motif, the family isdivided into two main branches, designated as the C-X-C chemokines(α-chemokines), and the C-C chemokines (β-chemokines), in which thefirst two conserved cysteines are separated by an intervening residue,or adjacent respectively (Baggiolini, M. and Dahinden, C. A., ImmunologyToday, 15:127-133 (1994)).

The C-X-C chemokines include a number of potent chemoattractants andactivators of neutrophils, such as interleukin 8 (IL-8), PF4 andneutrophil-activating peptide-2 (NAP-2). The C-C chemokines includeRANTES (Regulated on Activation, Normal T Expressed and Secreted), themacrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β), eotaxinand human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2, MCP-3), whichhave been characterized as chemoattractants and activators of monocytesor lymphocytes but do not appear to be chemoattractants for neutrophils.Chemokines, such as RANTES and MIP-1α, have been implicated in a widerange of human acute and chronic inflammatory diseases includingrespiratory diseases, such as asthma and allergic disorders.

The chemokine receptors are members of a superfamily of Gprotein-coupled receptors (GPCR) which share structural features thatreflect a common mechanism of action of signal transduction (Gerard, C.and Gerard, N. P., Annu Rev. Immunol., 12:775-808 (1994); Gerard, C. andGerard, N. P., Curr. Opin. Immunol., 6:140-145 (1994)). Conservedfeatures include seven hydrophobic domains spanning the plasma membrane,which are connected by hydrophilic extracellular and intracellularloops. The majority of the primary sequence homology occurs in thehydrophobic transmembrane regions with the hydrophilic regions beingmore diverse. The first receptor for the C-C chemokines that was clonedand expressed binds the chemokines MIP-1α and RANTES. Accordingly, thisMIP-1α/RANTES receptor was designated C-C chemokine receptor 1 (alsoreferred to as CCR-1; Neote, K., et al., Cell, 72:415-425 (1993); Horuk,R. et al., WO 94/11504, May 26, 1994; Gao, J.-I. et al., J. Exp. Med.,177:1421-1427 (1993)). Three receptors have been characterized whichbind and/or signal in response to RANTES: CCR3 mediates binding andsignaling of chemokines including eotaxin, RANTES, and MCP-3 (Ponath etal., J. Exp. Med., 183:2437 (1996)), CCR4 binds chemokines includingRANTES, MIP-1α, and MCP-1 (Power, et al., J. Biol. Chem., 270:19495(1995)), and CCR5 binds chemokines including MIP-1α, RANTES, and MIP-1β(Samson, et al., Biochem. 35: 3362-3367 (1996)). RANTES is a chemotacticchemokine for a variety of cell types, including monocytes, eosinophils,and a subset of T-cells. The responses of these different cells may notall be mediated by the same receptor, and it is possible that thereceptors CCR1, CCR4 and CCR5 will show some selectivity in receptordistribution and function between leukocyte types, as has already beenshown for CCR3 (Ponath et al.) . In particular, the ability of RANTES toinduce the directed migration of monocytes and a memory population ofcirculating T-cells (Schall, T. et al., Nature, 347:669-71 (1990))suggests this chemokine and its receptor(s) may play a critical role inchronic inflammatory diseases, since these diseases are characterized bydestructive infiltrates of T cells and monocytes.

Many existing drugs have been developed as antagonists of the receptorsfor biogenic amines, for example, as antagonists of the dopamine andhistamine receptors. No successful antagonists have yet been developedto the receptors for the larger proteins such as chemokines and C5a.Small molecule antagonists of the interaction between C-C chemokinereceptors and their ligands, including RANTES and MIP-1α, would providecompounds useful for inhibiting harmful inflammatory processes“triggered” by receptor ligand interaction, as well as valuable toolsfor the investigation of receptor-ligand interactions.

SUMMARY OF THE INVENTION

It has now been found that a class of small organic molecules areantagonists of chemokine receptor function and can inhibit leukocyteactivation and/or recruitment. An antagonist of chemokine receptorfunction is a molecule which can inhibit the binding and/or activationof one or more chemokines, including C-C chemokines such as RANTES,MIP-1α, MCP-2, MCP-3 and MCP-4 to one or more chemokine receptors onleukocytes and/or other cell types. As a consequence, processes andcellular responses mediated by chemokine receptors can be inhibited withthese small organic molecules. Based on this discovery, a method oftreating a disease associated with aberrant leukocyte recruitment and/oractivation is disclosed as well as a method of treating a diseasemediated by chemokine receptor function. The method comprisesadministering to a subject in need an effective amount of a compound orsmall organic molecule which is an antagonist of chemokine receptorfunction. Compounds or small organic molecules which have beenidentified as antagonists of chemokine receptor function are discussedin detail herein below, and can be used for the manufacture of amedicament for treating or for preventing a disease associated withaberrant leukocyte recruitment and/or activation. The invention alsorelates to the disclosed compounds and small organic molecules for usein treating or preventing a disease associated with aberrant leukocyterecruitment and/or activation. The invention also includespharmaceutical compositions comprising one or more of the compounds orsmall organic molecules which have been identified herein as antagonistsof chemokine function and a suitable pharmaceutical carrier. Theinvention further relates to novel compounds which can be used to treatan individual with a disease associated with aberrant leukocyterecruitment and/or activation and methods for their preparation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic showing the preparation of the compoundsrepresented by Structural Formula (I).

FIG. 2 is a schematic showing the preparation of the compoundsrepresented by Compound (VI-b).

FIG. 3 is a schematic showing the preparation of the compoundsrepresented by Structural Formula (I)

FIG. 4 is a schematic showing the preparation of representativecompounds of Structural Formula (I), wherein Ar¹ and/or Ar² can besubstituted with R⁴⁰.

FIG. 5 is a schematic showing the preparation of representativecompounds of Structural Formula (I), wherein Ar¹ and/or Ar² can besubstituted with —(O)_(u)—(CH₂)_(t)—COOR²⁰,—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰.

FIGS. 6A-6G show the structures of exemplary compounds of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to small molecule compounds which aremodulators of chemokine receptor function. In a preferred embodiment,the small molecule compounds are antagonists of chemokine receptorfunction. Accordingly, processes or cellular responses mediated by thebinding of a chemokine to a receptor can be inhibited (reduced orprevented, in whole or in part), including leukocyte migration, integrinactivation, transient increases in the concentration of intracellularfree calcium [Ca⁺⁺]_(i), and/or granule release of proinflammatorymediators.

The invention further relates to a method of treatment, includingprophylactic and therapeutic treatments, of a disease associated withaberrant leukocyte recruitment and/or activation or mediated bychemokines or chemokine receptor function, including chronicinflammatory disorders characterized by the presence of RANTES, MIP-1α,MCP-2, MCP-3 and/or MCP-4 responsive T cells, monocytes and/oreosinophils, including but not limited to diseases such as arthritis,psoriasis, multiple sclerosis, inflammatory bowel diseases such asulcerative colitis and Crohn's disease, rejection of transplanted organsand tissues (i.e., allograft rejection), graft versus host disease, aswell as allergies and asthma. Other diseases associated with aberrantleukocyte recruitment and/or activation which can be treated (includingprophylactic treatments) with the methods disclosed herein areinflammatory diseases associated with Human Immunodeficiency Virus (HIV)infection, e.g., AIDS associated encephalitis, AIDS relatedmaculopapular skin eruption, AIDS related interstitial pneumonia, AIDSrelated enteropathy, AIDS related periportal hepatic inflammation andAIDS related glomerulo nephritis. The method comprises administering tothe subject in need of treatment an effective amount of a compound(i.e., one or more compounds) which inhibits chemokine receptorfunction, inhibits the binding of a chemokine to leukocytes and/or othercell types, and/or which inhibits leukocyte migration to, and/oractivation at, sites of inflammation.

The invention further relates to methods of antagonizing a chemokinereceptor, such as CCR1, in a mammal comprising administering to themammal a compound as described herein.

According to the method, chemokine-mediated chemotaxis and/or activationof pro-inflammatory cells bearing receptors for chemokines can beinhibited. As used herein, “pro-inflammatory cells” includes but is notlimited to leukocytes, since chemokine receptors can be expressed onother cell types, such as neurons and epithelial cells.

While not wishing to be bound by any particular theory or mechanism, itis believed that compounds of the invention are antagonists of thechemokine receptor CCR1, and that therapeutic benefits derived from themethod of the invention are the result of antagonism of CCR1 function.Thus, the method and compounds of the invention can be used to treat amedical condition involving cells which express CCR1 on their surfaceand which respond to signals transduced through CCR1, as well as thespecific conditions recited above.

The antagonist of chemokine receptor function is represented byStructural Formula (I):

and physiologically acceptable salts thereof.

Ar¹ is a heteroaryl group, and

Ar² is a carbocyclic aromatic or heteroaryl group.

n is an integer, such as an integer from one to about four. Preferably,n is one, two or three. More preferably n is two. In alternativeembodiments, other aliphatic or aromatic spacer groups (L) can beemployed for (CH₂)_(n).

M is >NR² or >CR¹R². M is preferably >C(OH)R².

R¹ is —H, —OH, an aliphatic group, —O-(aliphatic group), —O-(substitutedaliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphaticgroup), —OC(O)-(aliphatic group) or —O—C(O)-(substituted aliphaticgroup), —COOH, —CN, —CO—NR³R⁴ or —NR³R⁴. R¹ is preferably —H or —OH.

R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group, a benzyl group, a substituted benzyl group,a non-aromatic heterocyclic group or a substituted non-aromaticheterocyclic group. R² is preferably an aromatic group or a substitutedaromatic group.

R³, R⁴, R⁵ and R⁶ are independently —H, an acyl group, a substitutedacyl group, an aliphatic group, a substituted aliphatic group, anaromatic group, a substituted aromatic group, a benzyl group, asubstituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group.

R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to whichthey are bonded, can alternatively form a substituted or unsubstitutednon-aromatic carbocyclic or heterocyclic ring.

Ar¹ and Ar² in Structural Formula (I) can be independently substitutedor unsubstituted. Suitable substituents are as described herein below.In one example, Ar¹ and/or Ar² is substituted with—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰.

u is zero or one.

t is an integer, such as an integer from zero to about three. Themethylene group, —(CH₂)_(t)—, can be substituted or unsubstituted.

R²⁰, R²¹ or R²² are independently —H, an aliphatic group, a substitutedaliphatic group, an aromatic group, a substituted aromatic group or anon-aromatic heterocyclic group. Alternatively, R²¹ and R²², takentogether with the nitrogen atom to which they are bonded, form anon-aromatic heterocyclic ring.

In one embodiment, Ar¹ is a 3-pyridyl group, Ar² is a carbocyclicaromatic or heteroaromatic group and Ar¹ and Ar² are independentlysubstituted or unsubstituted.

In a preferred embodiment the antagonist of chemokine receptor functionis represented by Structural Formula (II) , wherein Ar¹ is a 3-pyridylgroup, Ar² is a phenyl group and Ar¹ and Ar² are independentlysubstituted or unsubstituted.

Preferably Ar² in Structural Formula (II) bears a meta substituent, R⁴⁰,and the antagonist of chemokine receptor function is represented byStructural Formula (III):

wherein R⁴⁰ can be —OH, halogen, substituted or unsubstituted aliphaticgroup, substituted or unsubstituted aromatic group, —O-(aliphaticgroup), —O-(substituted aliphatic group), —O-(aromatic group),—O-(substituted aromatic group, electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u),—(CH₂)_(t)—NHC(O)—O—R²⁰.

u can be zero or one.

t is an integer, such as an integer from zero to about three.

R²⁰, R²¹ or R²² can independently be —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup or a non-aromatic heterocyclic group. Alternatively, R²¹ and R²²,taken together with the nitrogen atom to which they are bonded, form anon-aromatic heterocyclic ring.

Preferably R⁴⁰ is an aliphatic group, —O-(aliphatic group) or—O-(substituted aliphatic group). More preferably, R⁴⁰ is —O-alkyl, suchas —O—CH₃, —O—C₂H₅, —O—C₃H₇ or —O—C₄H₉.

Another embodiment provides novel compounds employed in these methods.

The double bond-containing compounds disclosed herein can be obtained asE- and Z-configurational isomers. It is expressly pointed out that theinvention includes compounds of the E-configuration and theZ-configuration around the double bond, and a method of treating asubject with compounds of the E-configuration, the Z-configuration, andmixtures thereof. Accordingly, in the structural formulas presentedherein, the symbol:

is used to represent both E-configuration and the Z-configuration.Preferably Ar¹ and the (CH₂)_(n) moiety are in the cis configuration.For example, the compounds can have the configuration of:

It is understood that one configuration can have greater activity thananother. The desired configuration can be determined by screening foractivity, employing the methods described herein.

Additionally, certain compounds of the invention may be obtained asdifferent sterioisomers (e.g., diastereomers and enantiomers). It ispointed out that the invention includes all isomeric forms and racemicmixtures of the disclosed compounds and a method of treating a subjectwith both pure isomers and mixtures thereof, including racemic mixtures.Again, it is understood that one sterioisomer may be more active thananother. The desired isomer can be determined by screening.

Also included in the present invention are physiologically acceptablesalts of the compounds represented by Structural Formulas (I) through(III). Salts of compounds containing an amine or other basic group canbe obtained, for example, by reacting with a suitable organic orinorganic acid, such as hydrogen chloride, hydrogen bromide, aceticacid, citric acid, perchloric acid and the like. Compounds with aquaternary ammonium group also contain a counteranion such as chloride,bromide, iodide, acetate, perchlorate and the like. Salts of compoundscontaining a carboxylic acid or other acidic functional group can beprepared by reacting with a suitable base, for example, a hydroxidebase. Salts of acidic functional groups contain a countercation such assodium, potassium, ammonium, calcium and the like.

As used herein, aliphatic groups include straight chained, branched orcyclic C₁-C₂₀ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation. For example, suitablealiphatic groups include substituted or unsubstituted linear, branchedor cyclic C₁-C₂₀ alkyl, alkenyl or alkynyl groups.

Aromatic groups include carbocyclic aromatic groups such as phenyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclicaromatic or heteroaryl groups such as N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl. Wherethese rings are fused, for example, to a non-aromatic or aromatic ring,the stated point of attachment can be either of the two fused bonds.

Aromatic groups also include fused polycyclic aromatic ring systems inwhich a carbocyclic aromatic ring or heteroaryl ring is fused to one ormore other rings. Examples include tetrahydronaphthyl, 2-benzothienyl,3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl,2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl,2-benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 1-isoquinolinyl,3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridinyl. Also includedwithin the scope of the term “aromatic group”, as it is used herein, isa group in which one or more carbocyclic aromatic rings and/orheteroaryl rings are fused to a cycloalkyl or non-aromatic heterocyclicring.

The term “non-aromatic ring” includes non-aromatic carbocyclic rings andnon-aromatic heterocyclic rings. Non-aromatic heterocyclic rings arenon-aromatic carbocyclic rings which include one or more heteroatomssuch as nitrogen, oxygen or sulfur in the ring. The ring can be five,six, seven or eight-membered and/or fused to another ring, such as acycloalkyl on aromatic ring. Examples of non-aromatic rings include, forexample, 3-1H-benzimidazol-2-one, 3-1-alkyl-benzimidazol-2-one,3-1-methyl-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahyrothiophenyl, 3-tetrahyrothiophenyl, 2-morpholino,3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituteddiazolonyl, 1-phthalimidyl, 1-3-alkyl-phthalimidyl, tetrahydronapthyl,benzocyclopentane, benzocyclohexane, benzoxane, benzopyrolidine,benzopiperidine, benzoxolane, benzothiolane, benzothiane,

Suitable substituents on an aliphatic group, aromatic group (carbocyclicand heteroaryl), non-aromatic heterocyclic ring or benzyl group include,for example, an electron withdrawing group, a halogen, —CN, —COOH, —OH,—CONR²⁴R²⁵, —NR²⁴R²⁵, —OS(O)₂NR²⁴R²⁵, —S(O)₂NR²⁴R²⁵, —SO₃H, —S(O)₂NH₂,guanidino, —(CH₂)_(t)—COOH, —(CH₂)_(t)—COOR²⁰, —(CH₂)_(t)—C(O)—NR²¹R²²,—Q—H, —Q-(aliphatic group), —Q-(substituted aliphatic group), —Q-(aryl),—Q—(CH₂)_(p)-(substituted or unsubstituted aromatic group) (p is aninteger from 1-5), —Q-(non-aromatic heterocyclic group) or—Q—(CH₂)_(p)-(non-aromatic heterocyclic group).

R²⁰, R²¹ or R²² are independently —H, an aliphatic group, a substitutedaliphatic group, an aromatic group, a substituted aromatic group,—NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromatic group) or—NHC(O)—O-(non-aromatic heterocyclic group) and wherein R²¹ and R²²,taken together with the nitrogen atom to which they are bonded, can forma non-aromatic heterocyclic ring.

t is an integer from zero to about three.

Q is —O—, —S—, —S(O)—, —S(O)₂ —, —OS(O)₂, —C (O)—, —OC(O)—, —C(O)O—,—C(O)C(O)—O—, —O—C(O)C(O)—, —C(O)NH—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—,—NH—C(O)—NH—, —S(O)₂NH—, —NHS(O)₂—, —N(R²³)—, —C(NR²³)NHNH— or—NHNHC(NR²³)—.

R²³ is —H, an aliphatic group, a benzyl group, an aryl group ornon-aromatic heterocyclic group.

R²⁴ and R²⁵ are independently —H, an aliphatic group, a benzyl group, anaryl group or non-aromatic heterocyclic group.

A substituted non-aromatic heterocyclic ring, benzyl group or aromaticgroup can also have an aliphatic or substituted aliphatic group as asubstituent. A substituted aliphatic group can also have an oxo group,epoxy group, non-aromatic heterocyclic ring, benzyl group, substitutedbenzyl group, aromatic group or substituted aromatic group as asubstituent. A substituted non-aromatic heterocyclic ring can also have═O, ═S, ═NH or ═N(aliphatic, aromatic or substituted aromatic group) asa substituent. A substituted aliphatic, substituted aromatic,substituted non-aromatic heterocyclic ring or substituted benzyl groupcan have more than one substituent.

Acyl groups include substituted and unsubstituted aliphatic carbonyl,aromatic carbonyl, aliphatic sulfonyl and aromatic sulfonyl.

Suitable electron withdrawing groups include, for example, alkylimines,alkylsulfonyl, carboxamido, carboxylic alkyl esters, —CH═NH, —CN, —NO₂and halogens.

A “subject” is preferably a bird or mammal, such as a human, but canalso be an animal in need of veterinary treatment, e.g., domesticanimals (e.g., dogs, cats, and the like), farm animals (e.g., cows,sheep, fowl, pigs, horses, and the like) and laboratory animals (e.g.,rats, mice, guinea pigs, and the like).

An “effective amount” of a compound is an amount which results in theinhibition of one or more processes mediated by the binding of achemokine to a receptor in a subject with a disease associated withaberrant leukocyte recruitment and/or activation. Examples of suchprocesses include leukocyte migration, integrin activation, transientincreases in the concentration of intracellular free calcium [Ca²⁺]_(i)and granule release of proinflammatory mediators. Alternatively, an“effective amount” of a compound is a quantity sufficient to achieve adesired therapeutic and/or prophylactic effect, such as an amount whichresults in the prevention of or a decrease in the symptoms associatedwith a disease associated with aberrant leukocyte recruitment and/oractivation.

The amount of compound administered to the individual will depend on thetype and severity of the disease and on the characteristics of theindividual, such as general health, age, sex, body weight and toleranceto drugs. It will also depend on the degree, severity and type ofdisease. The skilled artisan will be able to determine appropriatedosages depending on these and other factors. Typically, an effectiveamount of the compound can range from about 0.1 mg per day to about 100mg per day for an adult. Preferably, the dosage ranges from about 1 mgper day to about 100 mg per day. An antagonist of chemokine receptorfunction can also be administered in combination with one or moreadditional therapeutic agents, e.g. theophylline, β-adrenergicbronchodilators, corticosteroids, antihistamines, antiallergic agentsand the like.

The compound can be administered by any suitable route, including, forexample, orally in capsules, suspensions or tablets or by parenteraladministration. Parenteral administration can include, for example,systemic administration, such as by intramuscular, intravenous,subcutaneous, or intraperitoneal injection. The compound can also beadministered orally (e.g., dietary), transdermally, topically, byinhalation (e.g., intrabronchial, intranasal, oral inhalation orintranasal drops), or rectally, depending on the disease or condition tobe treated. Oral or parenteral administration are preferred modes ofadministration.

The compound can be administered to the individual in conjunction withan acceptable pharmaceutical carrier as part of a pharmaceuticalcomposition for treatment of HIV infection, inflammatory disease, or theother diseases discussed above. Formulation of a compound to beadministered will vary according to the route of administration selected(e.g., solution, emulsion, capsule). Suitable pharmaceutical carriersmay contain inert ingredients which do not interact with the compound.Standard pharmaceutical formulation techniques can be employed, such asthose described in Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa. Suitable pharmaceutical carriers for parenteraladministration include, for example, sterile water, physiologicalsaline, bacteriostatic saline (saline containing about 0.9% mg/ml benzylalcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactateand the like. Methods for encapsulating compositions (such as in acoating of hard gelatin or cyclodextran) are known in the art (Baker, etal., “Controlled Release of Biological Active Agents”, John Wiley andSons, 1986).

The activity of compounds of the present invention can be assessed usingsuitable assays, such as receptor binding assays and chemotaxis assays.For example, as described in the Exemplification Section, small moleculeantagonists of RANTES and MIP-1α binding have been identified utilizingTHP-1 cells which bind RANTES and chemotax in response to RANTES andMIP-1α as a model for leukocyte chemotaxis. Specifically, a highthrough-put receptor binding assay, which monitors ¹²⁵I-RANTES and¹²⁵I-MIP-1α binding to THP-1 cell membranes, was used to identify smallmolecule antagonists which block binding of RANTES and MIP-1α. Compoundsof the present invention can also be identified by virtue of theirability to inhibit the activation steps triggered by binding of achemokine to its receptor, such as chemotaxis, integrin activation andgranule mediator release. They can also be identified by virtue of theirability to block RANTES and MIP-1α mediated HL-60, T-cell, peripheralblood mononuclear cell, and eosinophil chemotactic response.

The compounds disclosed herein can be prepared accordingly to theschemes shown in FIGS. 1-5. The schemes are described in greater detailbelow.

FIG. 1 shows the preparation of compounds represented by StructuralFormula (I). L¹ is PPh₃Cl, PPh₃Br, PPh₃I or (EtO)₂P(O), L² is a suitableleaving group such as halogen, p-toluene sulfonate, mesylate, alkoxy,and phenoxy; Pg is a suitable protecting group such astetrahydropyranyl; and the other symbols are as defined above.

In Step 1 of FIG. 1, a Wittig reaction is carried out in a solvent suchas ether, or tetrahydrofuran (THF) in the presence of a base such assodium hydride, n-butyl lithium or lithium diisopropylamide (LDA) at 0°C. up to the reflux temperature for the solvent used for 5 minutes to 72h. Compounds represented by Formula II in FIG. 1 can be prepared bymethods disclosed in J. Med. Chem., 1992 (35) 2074-2084, the entireteachings of which are incorporated herein by reference.

In Step 2 of FIG. 1, deprotection is carried out with an acid in asolvent such as methanol at room temperature up to the refluxtemperature for the solvent used for 5 minutes to 72 h. Alternatively, acompound of represented by Formula V in FIG. 1 can be prepared directlyfrom step 1 without isolating an intermediate. The reaction mixtureobtained after the work up of the reaction described in step 1 can bedissolved in the solvent and reacted with the acid.

In Step 3 of FIG. 1, the hydroxy group can be converted to a leavinggroup by known methods. Compounds represented by Formula VI in FIG. 1can be prepared by methods disclosed in J. Med. Chem., 1992 (35)2074-2084 and J. Org. Chem., 1977 (42) 353.

In Step 4 of FIG. 1, an alkylation reaction is carried out in a solventsuch as acetone, methyl ethyl ketone, ethyl acetate, toluene,tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of abase such as potassium carbonate or sodium hydride and a catalyst suchas an alkali metal iodide at room temperature up to the refluxtemperature for the solvent used for 5 minutes to 72 h.

FIG. 2 shows the preparation of compounds represented by Compound(VI-b). In Step 1 of FIG. 2, a Grignard reaction may be carried out in asolvent such as ether, or tetrahydrofuran (THF) at 0° C. up to thereflux temperature for the solvent used for 5 minuets to 72 h. CompoundVII is available commercially.

In Step 2 of FIG. 2, bromination may be carried out with brominateagents such as hydrobromic acid, bromotrimethylsilane or borontribromide-methyl sulfide complex in a solvent such as acetic acid,dichloromethane or dichloroethane at room temperature up to the refluxtemperature for the solvent used for 5 minutes to 72 h.

FIG. 3 shows the preparation of compounds represented by StructuralFormula (I). In FIG. 3, a reductive amination may be carried out withreducing regents such as sodium cyanoborohydride, sodiumacetoxyborohydride or sodium borohydride in a solvent such as methanol,ethanol, tetrahydrofuran (THF), dichloromethane or dichloroethane atroom temperature up to the reflux temperature for the solvent used for 5minutes to 72 h.

FIG. 4 shows the preparation of representative compounds represented ofStructural Formula (I), wherein Ar¹ and/or Ar² can be substituted withR⁴⁰. In FIG. 4, an alkylation reaction may be carried out in a solventsuch as acetone, methyl ethyl ketone, ethyl acetate, toluene,tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of abase such as potassium carbonate or sodium hydride and a catalyst suchas an alkali metal iodide at room temperature up to the refluxtemperature for the solvent used for 5 minutes to 72 h.

FIG. 5 is a schematic showing the preparation of representativecompounds of Structural Formula (I), wherein Ar¹ and/or Ar² can besubstituted with —(O)_(u)—(CH₂)_(t)—COOR²⁰,—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰. InFIG. 5, the hydrolysis reaction may be carried out in a mixture ofaqueous alkali metal hydroxide solution and a solvent such as methanol,ethanol, tetrahydrofuran (THF) or dioxane at room temperature up to thereflux temperature for the solvent used for 5 minutes to 72 h. Theacylation reaction can be carried out using dicyclohexylcarbodiimide(DCC) or (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (DEC) in asolvent such as tetrahydrofuran (THF), dimethylformamide (DMF) ormethylene chloride in the presence of a base such as pyridine ortriethylamine (when necessary) at temperatures of 0 to 100° C. for 5minutes to 72 h.

Although FIGS. 1-5 show the preparation of compounds in which Ar¹ is3-pyridyl and Ar² is phenyl, analogous compounds with other heteroarylgroups for Ar¹ and/or Ar² can be prepared by using starting materialswith heteroaryl groups in the corresponding positions. These startingmaterials can be prepared according to methods which are known to thoseof skill in the art.

The invention is illustrated by the following examples which are notintended to be limiting in any way.

EXEMPLIFICATION Example 14-(4-Chlorophenyl)-1-[4-(3-methoxyphenyl)-4-(3-pyridinyl)-3-butenyl]piperidin-4-ol

Step 1

To a solution of (3-methoxyphenyl)-(3-pyridinyl)methanone (500 mg) inTHF (10 ml) was added 1.1M cyclopropylmagnesium bromide THF solution (2ml) at 0° C. The reaction mixture was warmed to room temperature, andstirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate wereadded to the reaction mixture, the organic layer was separated andwashed with saturated aqueous sodium chloride, and dried with magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was filtered and washed with ethyl acetate-hexane (1:2) to givecyclopropyl-(3-methoxyphenyl)-(3-pyridinyl)methanol (470 mg).

¹H-NMR (CDCl₃) δ: 0.45-0.59(4H,m), 1.48-1.61(1H,m), 3.65(1H,brs),3.71(3H,s), 6.78(1H,dd), 6.92-7.22(4H,m), 7.69(1H,dd), 8.27(1H,dd),8.55(1H,d).

Step 2

To a solution of the product of step 1 (470 mg) in acetic acid (5 ml)was added 48% aqueous HBr (3 ml) at 10° C. The reaction mixture waswarmed to room temperature, and stirred for 12 hours. Water and ethylacetate were added to the reaction mixture and neutralized with diluteNaOH solution. The organic layer was separated and washed with saturatedaqueous sodium chloride, and dried over magnesium sulfate. The solventwas distilled off under reduced pressure. The residue was purified bysilica gel chromatography eluting with ethyl acetate-hexane (1:4) togive 4-bromo-1-(3-methoxyphenyl)-1-(3-pyridinyl)-1-butene (560 mg).

¹H-NMR (CDCl₃) δ: 2.66-2.74(2H,m), 3.41-3.46(2H,m), 3.67(0.6×3H,s),3.79(0.4×3H,s), 6.15-6.18(1H,m), 6.73-6.80(3H,m), 7.17-7.47(3H,m),8.46-8.64(2H,m).

Step 3

To a solution the product of step 2 (500 mg) in DMF (20 ml) were added4-(4-chlorophenyl)-4-hydroxypiperidine (500 mg), potassium carbonate(430 mg), potassium iodide (130 mg) and the mixture was stirred at roomtemperature for 12 hours. Water and ethyl acetate were added to thereaction mixture, the organic layer was separated and washed withsaturated aqueous sodium chloride, and dried with magnesium sulfate. Thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel chromatography eluting with methylenechloride-methanol (10:1) to give the titled compound as majorregioisomer (225 mg) and minor one (140 mg)

Major Isomer

¹H-NMR (CDCl₃) δ: 1.65-1.78(2H,m), 1.98-2.83(11H,m), 3.79(3H,s),6.22(1H,t), 6.75-6.84(4H,m), 7.18-7.57(6H,m), 8.42(1H,d), 8.50(1H,dd).MS m/z: 449 (M+1).

Minor Isomer

¹H-NMR (CDCl₃) δ: 1.65-1.79(2H,m), 2.08-2.88(11H,m), 3.79(3H,s),6.12(1H,t), 6.68-6.94(4H,m), 7.15-7.53(6H,m), 8.40(1H,dd) , 8.53(1H,d)MS m/z: 449 (M+1).

Example 24-(4-Chlorophenyl)-1-[4-phenyl-4-(3-pyridinyl)-3-butenyl]piperidin-4-ol

The titled compound was prepared by following the procedure of example1, but replacing (3-methoxyphenyl)-(3-pyridinyl)methanone withphenyl-(3-pyridinyl)methanone.

Major Isomer

¹H-NMR (CDCl₃) δ: 1.67-1.72 (2H,m) , 2.07-2.19(3H,m) , 2.31-2.61(6H,m),2.75-2.80(2H,m), 6.18(1H,t), 7.16-7.48(11H, m) , 8.44 (1H,d) ,8.49(1H,dd) MS m/z: 419 (M+1).

Minor Isomer

¹H-NMR (CDCl₃) δ: 1.69-1.74(2H,m) , 2.18-2.23(3H,m), 2.43-2.66(6H,m),2.82-2.86(2H,m), 6.18(1H,t), 7.16-7.48(11H,m), 8.44(1H,dd), 8.51(1H,d).MS m/z: 419 (M+1).

Example 34-(4-Chlorophenyl)-1-[4-(2,5-dimethoxyphenyl)-4-(3-pyridinyl)-3-butenyl]piperidin-4-ol

The titled compound was prepared by following the procedure of example1, but replacing (3-methoxyphenyl)-(3-pyridinyl)methanone with(2,5-dimethoxyphenyl)-(3-pyridinyl)methanone.

Major Isomer

¹H-NMR (CDCl₃) δ: 1.62-1.79(2H,m), 1.97-2.18(2H,m), 2.32-2.81(9H,m)3.47(3H,s), 3.79(3H,s), 5.92(1H,t), 6.68-6.82(3H,m), 7.11-7.49(6H,m),8.35(1H,dd), 8.41(1H,d). MS m/z: 479 (M+1).

Minor Isomer

¹H-NMR (CDCl₃) δ: 1.62-1.79(2H,m), 2.01-2.20(2H,m), 2.28-2.81(9H,m)3.49(3H,s), 3.80(3H,s), 5.91(1H,t), 6.70-6.84(3H,m), 7.12-7.50(6H,m),8.35(1H,dd), 8.41(1H,d). MS m/z: 479 (M+1)

Example 41-[4-(2-Bromo-4-pyridinyl)-4-(3-pyridinyl)-3-butenyl]-4-(4-chlorophenyl)piperidin-4-ol

The titled compound was prepared by following the procedure of example1, but replacing (3-methoxyphenyl)-(3-pyridinyl)methanone with(2-bromo-4-pyridinyl)-(3-pyridinyl)methanone.

¹H-NMR (CDCl₃) δ: 1.65-1.70(2H,m), 1.92-2.18(5H,m), 2.38-2.54(4H,m),2.67-2.72(2H,m), 6.31(1H,t), 7.14-7.41(7H,m), 8.38-8.41(2H,m),8.52(1H,d), 8.75(1H,s). MS m/z: 500 (M+1).

Examples 5-90 can be prepared by the schemes set forth is FIGS. 1-5 andthe procedures described above.

Example 91 Membrane Preparations for Chemokine Binding and BindingAssays

Membranes were prepared from THP-1 cells (ATCC #TIB202). Cells wereharvested by centrifugation, washed twice with PBS (phosphate-bufferedsaline), and the cell pellets were frozen at −70 to −85° C. The frozenpellet was thawed in ice-cold lysis buffer consisting of 5 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethane-sulfonic acid) pH 7.5, 2 mM EDTA(ethylenediaminetetraacetic acid), 5 μg/ml each aprotinin, leupeptin,and chymostatin (protease inhibitors), and 100 μg/ml PMSF (phenylmethane sulfonyl fluoride—also a protease inhibitor), at a concentrationof 1 to 5×10⁷ cells/ml. This procedure results in cell lysis. Thesuspension was mixed well to resuspend all of the frozen cell pellet.Nuclei and cell debris were removed by centrifugation of 400×g for 10minutes at 4° C. The supernatant was transferred to a fresh tube and themembrane fragments were collected by centrifugation at 25,000×g for 30minutes at 4° C. The supernatant was aspirated and the pellet wasresuspended in freezing buffer consisting of 10 mM HEPES pH 7.5, 300 mMsucrose, 1 μg/ml each aprotinin, leupeptin, and chymostatin, and 10μg/ml PMSF (approximately 0.1 ml per each 10⁸ cells) . All clumps wereresolved using a minihomogenizer, and the total protein concentrationwas determined using a protein assay kit (Bio-Rad, Hercules, Calif., cat#500-0002). The membrane solution was then aliquoted and frozen at −70to −85° C. until needed.

Binding Assays—utilized the membranes described above. Membrane protein(2 to 20 μg total membrane protein) was incubated with 0.1 to 0.2 nM¹²⁵I-labeled RANTES or MIP-1α with or without unlabeled competitor(RANTES or MIP-1α) or various concentrations of compounds. The bindingreactions were performed in 60 to 100 μl of a binding buffer consistingof 10 mM HEPES pH 7.2, 1 mM CaCl₂, 5 mM MgCl₂, and 0.5% BSA (bovineserum albumin), for 60 min at room temperature. The binding reactionswere terminated by harvesting the membranes by rapid filtration throughglass fiber filters (GF/B or GF/C, Packard) which were presoaked in 0.3%polyethyleneimine. The filters were rinsed with approximately 600 μl ofbinding buffer containing 0.5 M NaCl, dried, and the amount of boundradioactivity was determined by scintillation counting in a Topcountbeta-plate counter.

The activities of test compounds are reported in the Table below as IC₅₀values or the inhibitor concentration required for 50% inhibition ofspecific binding in receptor binding assays using ¹²⁵I-RANTES or¹²⁵MIP-1α as ligand and THP-1 cell membranes. Specific binding isdefined as the total binding minus the non-specific binding;non-specific binding is the amount of cpm still detected in the presenceof excess unlabeled Rantes or ¹²⁵MIP-1α.

TABLE BIOLOGICAL DATA Example IC₅₀ (μM) 1 <1 2 <1 3 <1 4 >1

EQUIVALENTS

Those skilled in the art will be able to recognize, or be able toascertain, using no more than routine experimentation, many equivalentsto the specific embodiments of the invention described herein. Suchequivalents are intended to be encompassed by the following claims.

What is claimed is:
 1. A method of treating a disease associated withaberrant leukocyte recruitment and/or activation mediated by chemokinereceptor function comprising administering to a subject in need thereofan effective amount of a compound represented by the followingstructural formula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic or group; n is an integer from one tofour; M is >CR¹R²; R¹is —H, —OH, an aliphatic group, —O-(aliphaticgroup), —O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —CN, —COOH, —CO—NR³R⁴ or —NR³R⁴;R² is —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, asubstituted or unsubstituted C₂-C₂₀ linear alkyl, alkenyl or alkynylgroup, a substituted or unsubstituted C₃-C₂₀ branched alkyl or alkenylgroup, a substituted or unsubstituted C₄-C₂₀ branched alkynyl group, asubstituted or unsubstituted C₃-C₂₀ cyclic alkyl or alkenyl group, asubstituted or unsubstituted C₉-C₂₀ cyclic alkynyl group, an aromaticgroup, a substituted aromatic group, a benzyl group, a substitutedbenzyl group, a non-aromatic heterocyclic group or a substitutednon-aromatic heterocyclic group; wherein: said acyl group is analiphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromaticsulfonyl; and R³, R⁴, R⁵ and R⁶ are independently —H, an aliphaticgroup, a substituted aliphatic group, an aromatic group, a substitutedaromatic group, a benzyl group, a substituted benzyl group, anon-aromatic heterocyclic group or a substituted non-aromaticheterocyclic group; or R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken togetherwith the atom to which they are bonded, form a substituted orunsubstituted non-aromatic heterocyclic ring.
 2. The method of claim 1wherein: Ar¹ or Ar² is substituted with —OH, a halogen, —O-(aliphaticgroup), —O-(substituted aliphatic group), —O-(aromatic group),—O-(substituted aromatic group), an electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰; wherein: u is zero or one; t is aninteger from zero to three; R²⁰, R²¹ or R²² are independently —H, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group or a non-aromatic heterocyclic group; or R²¹and R²², taken together with the nitrogen atom to which they are bonded,form a non-aromatic heterocyclic ring.
 3. The method of claim 1 whereinR¹ is —H or —OH.
 4. The method of claim 1 wherein R² is a substituted orunsubstituted aromatic group.
 5. The method of claim 1 wherein: Ar¹ is asubstituted or unsubstituted 3-pyridyl group.
 6. The method of claim 5wherein: Ar¹ or Ar² is substituted with —OH, a halogen, —O-(aliphaticgroup), —O-(substituted aliphatic group), —O-(aromatic group),—O-(substituted aromatic group), an electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰; wherein: u is zero or one; t is aninteger from zero to three; R²⁰, R²¹ or R²² are independently —H, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group or a non-aromatic heterocyclic group; or R²¹and R²², taken together with the nitrogen atom to which they are bonded,form a non-aromatic heterocyclic ring.
 7. The method of claim 5 whereinAr² is a substituted or unsubstituted phenyl group.
 8. The method ofclaim 7 wherein said phenyl group is substituted with —OH, a halogen,—O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromaticgroup), —O-(substituted aromatic group), an electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰; wherein: u is zero or one; t is aninteger from zero to three; R²⁰, R²¹ or R²² are independently —H, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group or a non-aromatic heterocyclic group; or R²¹and R²², taken together with the nitrogen atom to which they are bonded,form a non-aromatic heterocyclic ring.
 9. A method of treating a diseaseassociated with aberrant leukocyte recruitment and/or activationmediated by chemokine receptor function comprising administering to asubject in need thereof an effective amount of a compound represented bythe following structural formula:

or physiologically acceptable salt thereof, wherein: n is an integerfrom one to four; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —SH,—S-(aliphatic group), —S-(substituted aliphatic group),—OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —CN,—COOH, —CO—NR³R⁴ or —NR³R⁴; R² is —OH, an acyl group, a substituted acylgroup, —NR⁵R⁶, a substituted or unsubstituted C₂-C₂₀ linear alkyl,alkenyl or alkynyl group, a substituted or unsubstituted C₃-C₂₀ branchedalkyl or alkenyl group, a substituted or unsubstituted C₄-C₂₀ branchedalkynyl group, a substituted or unsubstituted C₃-C₂₀ cyclic alkyl oralkenyl group, a substituted or unsubstituted C₉-C₂₀ cyclic alkynylgroup, an aromatic group, a substituted aromatic group, a benzyl group,a substituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; wherein: said acyl group isan aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromaticsulfonyl; R³, R⁴, R⁵ and R⁶ are independently —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup, a benzyl group, a substituted benzyl group, a non-aromaticheterocyclic group or a substituted non-aromatic heterocyclic group; orR¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to whichthey are bonded, form a substituted or unsubstituted non-aromaticheterocyclic ring; and R⁴⁰ is —OH, halogen, aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromaticgroup), —O-(substituted aromatic group), an electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰; wherein: u is zero or one; t is aninteger from zero to three; R²⁰, R²¹ or R²² are independently —H, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group or a non-aromatic heterocyclic group; or R²¹and R²², taken together with the nitrogen atom to which they are bonded,form a non-aromatic heterocyclic ring.
 10. The method of claim 9 whereinR⁴⁰ is —O-alkyl.
 11. The method of claim 9 wherein: R¹ is —H or —OH; R²is a substituted or unsubstituted aromatic group; and n is two.
 12. Themethod of claim 11 wherein R⁴⁰ is —O—CH₃.
 13. A compound represented bythe following structural formula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic; n is an integer from one to four; Mis >CR¹R²; R¹ is —H, —OH, an aliphatic group, —O-(aliphatic group),—O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —CN, —COOH, —CO—NR³R⁴ or —NR³R⁴;R² is —OH, an acyl group, a substituted acyl group, —NR⁵R⁶,a substitutedor unsubstituted C₂-C₂₀ linear alkyl, alkenyl or alkynyl group, asubstituted or unsubstituted C₃-C₂₀ branched alkyl or alkenyl group, asubstituted or unsubstituted C₄-C₂₀ branched alkynyl group, asubstituted or unsubstituted C₃-C₂₀ cyclic alkyl or alkenyl group, asubstituted or unsubstituted C₉-C₂₀ cyclic alkynyl group, an aromaticgroup, a substituted aromatic group, a benzyl group, a substitutedbenzyl group; wherein: said acyl group is an aliphatic carbonyl,aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl; and R³, R⁴,R⁵ and R⁶ are independently —H, an aliphatic group, a substitutedaliphatic group, an aromatic group, a substituted aromatic group, abenzyl group, a substituted benzyl group, a non-aromatic heterocyclicgroup or a substituted non-aromatic heterocyclic group; or R¹ and R², R³and R⁴, or R⁵ and R⁶ taken together with the atom to which they arebonded, form a substituted or unsubstituted non-aromatic heterocyclicring.
 14. The compound of claim 13 wherein: Ar¹ or Ar² is substitutedwith —OH, a halogen, —O-(aliphatic group), —O-(substituted aliphaticgroup), —O-(aromatic group), —O-(substituted aromatic group), anelectron withdrawing group, —(O)_(u)—(CH₂)_(t)—COOR²⁰,—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰;wherein: u is zero or one; t is an integer from zero to three; R²⁰, R²¹or R²² are independently —H, an aliphatic group, a substituted aliphaticgroup, an aromatic group, a substituted aromatic group or a non-aromaticheterocyclic group; or R²¹ and R²², taken together with the nitrogenatom to which they are bonded, form a non-aromatic heterocyclic ring.15. The compound of claim 13 wherein R¹ is —H or —OH.
 16. The compoundof claim 13 wherein R² is a substituted or unsubstituted aromatic group.17. The compound of claim 13 wherein: Ar¹ is a substituted orunsubstituted 3-pyridyl group.
 18. The compound of claim 17 wherein: Ar¹or Ar² is substituted with —OH, a halogen, —O-(aliphatic group),—O-(substituted aliphatic group), —O-(aromatic group), —O-(substitutedaromatic group), an electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰; wherein: u is zero or one; t is aninteger from zero to three; R²⁰, R²¹ or R²² are independently —H, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group or a non-aromatic heterocyclic group; or R²¹and R²², taken together with the nitrogen atom to which they are bonded,form a non-aromatic heterocyclic ring.
 19. The compound of claim 17wherein Ar² is a substituted or unsubstituted phenyl group.
 20. Thecompound of claim 19 wherein said phenyl group is substituted with —OH,a halogen, —O-(aliphatic group), —O-(substituted aliphatic group),—O-(aromatic group), —O-(substituted aromatic group), an electronwithdrawing group, —(O)_(u)—(CH₂)_(t)—COOR²⁰,—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰;wherein: u is zero or one; t is an integer from zero to three; R²⁰, R²¹or R²² are independently —H, an aliphatic group, a substituted aliphaticgroup, an aromatic group, a substituted aromatic group or a non-aromaticheterocyclic group; or R²¹ and R²², taken together with the nitrogenatom to which they are bonded, form a non-aromatic heterocyclic ring.21. A compound represented by the following structural formula:

or physiologically acceptable salt thereof, wherein: n is an integerfrom one to four; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —SH,—S-(aliphatic group), —S-(substituted aliphatic group),—OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —CN,—COOH, —CO—NR³R⁴ or —NR³R⁴; R² is —OH, an acyl group, a substituted acylgroup, —NR⁵R⁶, a substituted or unsubstituted C₂-C₂₀ linear alkyl,alkenyl or alkynyl group, a substituted or unsubstituted C₃-C₂₀ branchedalkyl or alkenyl group, a substituted or unsubstituted C₄-C₂₀ branchedalkynyl group, a substituted or unsubstituted C₃-C₂₀ cyclic alkyl oralkenyl group, a substituted or unsubstituted C₉-C₂₀ cyclic alkynylgroup, an aromatic group, a substituted aromatic group, a benzyl group,a substituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; wherein: R³, R⁴, R⁵ and R⁶are independently —H, an aliphatic group, a substituted aliphatic group,an aromatic group, a substituted aromatic group, a benzyl group, asubstituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; or R¹ and R², R³ and R⁴, orR⁵ and R⁶ taken together with the atom to which they are bonded, form asubstituted or unsubstituted non-aromatic heterocyclic ring; said acylgroup is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl oraromatic sulfonyl; and R⁴⁰ is —OH, halogen, aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromaticgroup), —O-(substituted aromatic group), an electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰; wherein: u is zero or one; t is aninteger from zero to three; R²⁰, R²¹ or R²² are independently —H, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group or a non-aromatic heterocyclic group; or R²¹and R²², taken together with the nitrogen atom to which they are bonded,form a non-aromatic heterocyclic ring.
 22. The compound of claim 21wherein R⁴⁰ is —O-alkyl.
 23. The compound of claim 21 wherein: R¹ is —Hor —OH; R² is a substituted or unsubstituted aromatic group; and n istwo.
 24. The compound of claim 23 wherein R⁴⁰ is —O—CH₃.
 25. A method ofantagonizing a chemokine receptor in a mammal in need thereof comprisingadministering to said mammal a chemokine receptor antagonizing amount ofa compound represented by:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic group; n is an integer from one tofour; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group, —O-(aliphaticgroup), —O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —CN, —COOH, —CO—NR³R⁴ or —NR³R⁴;and R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group, a benzyl group, a substituted benzyl group,a non-aromatic heterocyclic group or a substituted non-aromaticheterocyclic group; wherein: said acyl group is an aliphatic carbonylaromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl; R³, R⁴, R⁵and R⁶ are independently —H, an aliphatic group, a substituted aliphaticgroup, an aromatic group, a substituted aromatic group, a benzyl group,a substituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; or R¹ and R², R³ and R⁴, orR⁵ and R⁶ taken together with the atom to which they are bonded, form asubstituted or unsubstituted non-aromatic heterocyclic ring.
 26. Amethod of treating a disease associated with aberrant leukocyterecruitment and/or activation mediated by chemokine receptor function,said disease being selected from the group consisting of arthritis,psoriasis, multiple sclerosis, rejection of a transplanted organ ortissue, graft versus host disease, ulcerative colitis, Crohn's disease,allergy, asthma, AIDS associated encephalitis, AIDS relatedmaculopapular skin eruption, AIDS related interstitial pneumonia, AIDSrelated enteropathy, AIDS related periportal hepatic inflammation andAIDS related glomerulo nephritis, comprising administering to a subjectin need thereof an effective amount of a compound represented by thefollowing structural formula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic group; n is an integer from one tofour; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group, —O-(aliphaticgroup), —O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —CN, —COOH, —CO—NR³R⁴ or —NR³R⁴;R² is —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, asubstituted or unsubstituted C₂-C₂₀ linear alkyl, alkenyl or alkynylgroup, a substituted or unsubstituted C₃-C₂₀ branched alkyl or alkenylgroup a substituted or unsubstituted C₄-C₂₀ branched alkynyl group asubstituted or unsubstituted C₃-C₂₀ cyclic alkyl or alkenyl group, asubstituted or unsubstituted C₉-C₂₀ cyclic alkynyl group, an aromaticgroup, a substituted aromatic group, a benzyl group, a substitutedbenzyl group, a non-aromatic heterocyclic group or a substitutednon-aromatic heterocyclic group; wherein: said acyl group is analiphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromaticsulfonyl; and R³, R⁴, R⁵ and R⁶ are independently —H, an aliphaticgroup, a substituted aliphatic group, an aromatic group, a substitutedaromatic group, a benzyl group, a substituted benzyl group, anon-aromatic heterocyclic group or a substituted non-aromaticheterocyclic group; or R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken togetherwith the atom to which they are bonded, form a substituted orunsubstituted non-aromatic heterocyclic ring.
 27. The method of claim 25wherein Ar² is a substituted or unsubstituted phenyl group.
 28. Themethod of claim 25 wherein R¹ is —H or —OH.
 29. The method of claim 25wherein R² is a substituted or unsubstituted aromatic group.
 30. Themethod of claim 25 wherein: Ar¹ is a substituted or unsubstituted3-pyridyl group.
 31. A method of antagonizing a chemokine receptor in amammal in need thereof, comprising administering to said mammal aneffective amount of a compound represented by:

or physiologically acceptable salt thereof, wherein: n is an integerfrom one to four; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —SH,—S-(aliphatic group), —S-(substituted aliphatic group),—OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —CN,—COOH, —CO—NR³R⁴ or —NR³R⁴; and R² is —H, —OH, an acyl group, asubstituted acyl group, —NR⁵R⁶, an aliphatic group, a substitutedaliphatic group, an aromatic group, a substituted aromatic group, abenzyl group, a substituted benzyl group, a non-aromatic heterocyclicgroup or a substituted non-aromatic heterocyclic group; wherein: saidacyl group is an aliphatic carbonyl, aromatic carbonyl, aliphaticsulfonyl or aromatic sulfonyl; R³, R⁴, R⁵ and R⁶ are independently —H,an aliphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group, a benzyl group, a substituted benzyl group,a non-aromatic heterocyclic group or a substituted non-aromaticheterocyclic group; or R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken togetherwith the atom to which they are bonded, form a substituted orunsubstituted non-aromatic heterocyclic ring; and R⁴⁰ is —OH, halogen,aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group),—O-(aromatic group), —O-(substituted aromatic group), an electronwithdrawing group, —(O)_(u)—(CH₂)_(t)—COOR²⁰,—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰;wherein: u is zero or one; t is an integer from zero to three; R²⁰, R²¹or R²² are independently —H, an aliphatic group, a substituted aliphaticgroup, an aromatic group, a substituted aromatic group or a non-aromaticheterocyclic group; or R²¹ and R²², taken together with the nitrogenatom to which they are bonded, form a non-aromatic heterocyclic ring.32. The method of claim 31 wherein R⁴⁰ is —O-alkyl.
 33. The method ofclaim 31 wherein R⁴⁰ is —(O)_(u)—(CH₂)_(t)—COOR²⁰, wherein u is zero, tis zero and R²⁰ is —H.
 34. The method of claim 31 wherein: R¹ is —H or—OH; and R² is a substituted or unsubstituted aromatic group.
 35. Acompound represented by the following structural formula:

or physiologically acceptable salt thereof, wherein: n is an integerfrom one to four; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —SH,—S-(aliphatic group), —S-(substituted aliphatic group),—OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —CN,—COOH, —CO—NR³R⁴ or —NR³R⁴; R² is —OH, an acyl group, a substituted acylgroup, —NR⁵R⁶, a substituted or unsubstituted C₂-C₂₀ linear alkyl,alkenyl or alkynyl group, a substituted or unsubstituted C₃-C₂₀ branchedalkyl or alkenyl group, a substituted or unsubstituted C₄-C₂₀ branchedalkynyl group, a substituted or unsubstituted C₃-C₂₀ cyclic alkyl oralkenyl group, a substituted or unsubstituted C₉-C₂₀ cyclic alkynylgroup, an aromatic group, a substituted aromatic group, a benzyl group,a substituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; wherein: said acyl group isan aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromaticsulfonyl; R³, R⁴, R⁵ and R⁶ are independently —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup, a benzyl group, a substituted benzyl group, a non-aromaticheterocyclic group or a substituted non-aromatic heterocyclic group; orR¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to whichthey are bonded, form a substituted or unsubstituted non-aromaticheterocyclic ring; R⁴⁰ is —(O)_(u)—(CH₂)_(t)—COOR²⁰; wherein: u is zero;t is zero; and R²⁰ is —H.
 36. A compound represented by the followingstructural formula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic group; n is an integer from one tofour; M is >CR¹R²; R¹ is —H or —OH; R² is phenyl, substituted phenyl,pyridyl, substituted pyridyl, napthyl, substituted napthyl, quinolinyl,substituted quinolinyl, anthracyl, substituted anthracyl, benzyl orsubstituted benzyl; or R¹ and R² taken together with the atom to whichthey are bonded, form a substituted or unsubstituted non-aromaticheterocyclic ring.
 37. A compound represented by the followingstructural formula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic group; n is an integer from one tofour; M is >CR¹R²; R¹ is —H or —OH; and R² is a substituted orunsubstituted non-aromatic heterocyclic group, wherein said non-aromaticheterocyclic group is tetrahydrofuranyl, tetrahyrothiophenyl,morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl,thiazolidinyl, diazolonyl, phthalimidyl, benzoxanyl, benzopyrolidinyl,benzopiperidinyl, benzoxolanyl, benzothiolanyl and benzothianyl.
 38. Amethod of treating a disease mediated by chemokine receptor function,comprising administering to a subject in need thereof an effectiveamount of a compound represented by the following structural formula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic group; n is an integer from one tofour; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group, —O-(aliphaticgroup), —O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —CN, —COOH, —CO—NR³R⁴ or —NR³R⁴;R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group, a benzyl group, a substituted benzyl group,a non-aromatic heterocyclic group or a substituted non-aromaticheterocyclic group; wherein: said acyl group is an aliphatic carbonyl,aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl; and R³, R⁴,R⁵ and R⁶ are independently —H, an aliphatic group, a substitutedaliphatic group, an aromatic group, a substituted aromatic group, abenzyl group, a substituted benzyl group, a non-aromatic heterocyclicgroup or a substituted non-aromatic heterocyclic group; or R¹ and R², R³and R⁴, or R⁵ and R⁶ taken together with the atom to which they arebonded, form a substituted or unsubstituted non-aromatic heterocyclicring.
 39. A method of treating a disease associated with aberrantleukocyte recruitment and/or activation mediated by chemokine receptorfunction comprising administering to a subject in need thereof aneffective amount of a compound represented by the following structuralformula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic or group; n is an integer from one tofour; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group, —O-(aliphaticgroup), —O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —CN, —COOH, —CO—NR³R⁴ or —NR³R⁴;R² is —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, an aliphaticgroup, a substituted aliphatic group, an aromatic group, a substitutedaromatic group, a benzyl group, a substituted benzyl group, anon-aromatic heterocyclic group or a substituted non-aromaticheterocyclic group; wherein: said acyl group is an aliphatic carbonyl,aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl; and R³, R⁴,R⁵ and R⁶ are independently —H, an aliphatic group, a substitutedaliphatic group, an aromatic group, a substituted aromatic group, abenzyl group, a substituted benzyl group, a non-aromatic heterocyclicgroup or a substituted non-aromatic heterocyclic group; or R¹ and R², R³and R⁴, or R⁵ and R⁶ taken together with the atom to which they arebonded, form a substituted or unsubstituted non-aromatic heterocyclicring; with the proviso that when R¹ is —H, R² is not methyl.
 40. Amethod of treating a disease associated with aberrant leukocyterecruitment and/or activation mediated chemokine receptor functioncomprising administering to a subject in need thereof an effectiveamount of a compound represented by the following structural formula:

or physiologically acceptable salt thereof, wherein: n is an integerfrom one to four; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —SH,—S-(aliphatic group), —S-(substituted aliphatic group),—OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —CN,—COOH, —CO—NR³R⁴ or —NR³R⁴; and R² is —OH, an acyl group, a substitutedacyl group, —NR⁵R⁶, an aliphatic group, a substituted aliphatic group,an aromatic group, a substituted aromatic group, a benzyl group, asubstituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; wherein: said acyl group isan aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromaticsulfonyl; R³, R⁴, R⁵ and R⁶ are independently —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup, a benzyl group, a substituted benzyl group, a non-aromaticheterocyclic group or a substituted non-aromatic heterocyclic group; orR¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to whichthey are bonded, form a substituted or unsubstituted non-aromaticheterocyclic ring; and R⁴⁰ is —OH, halogen, aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromaticgroup), —O-(substituted aromatic group), an electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰; wherein: u is zero or one; t is aninteger from zero to three; R²⁰, R²¹ or R²² are independently —H, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group or a non-aromatic heterocyclic group; or R²¹and R²², taken together with the nitrogen atom to which they are bonded,form a non-aromatic heterocyclic ring; with the proviso that when R¹ is—H, R² is not methyl.
 41. A compound represented by the followingstructural formula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic; n is an integer from one to four; Mis >CR¹R²; R¹ is —H, —OH, an aliphatic group, —O-(aliphatic group),—O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —CN, —COOH, —CO—NR³R⁴ or —NR³R⁴;and R² is —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group, a benzyl group, a substituted benzyl group;wherein: said acyl group is an aliphatic carbonyl, aromatic carbonyl,aliphatic sulfonyl or aromatic sulfonyl; R³, R⁴, R⁵ and R⁶ areindependently —H, an aliphatic group, a substituted aliphatic group, anaromatic group, a substituted aromatic group, a benzyl group, asubstituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; or R¹ and R², R³ and R⁴, orR⁵ and R⁶ taken together with the atom to which they are bonded, form asubstituted or unsubstituted non-aromatic heterocyclic ring; with theproviso that when R¹ is —H, R² is not methyl.
 42. A compound representedby the following structural formula:

or physiologically acceptable salt thereof, wherein: n is an integerfrom one to four; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —SH,—S-(aliphatic group), —S-(substituted aliphatic group),—OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —CN,—COOH, —CO—NR³R⁴ or —NR³R⁴; and R² is —OH, an acyl group, a substitutedacyl group, —NR⁵R⁶, an aliphatic group, a substituted aliphatic group,an aromatic group, a substituted aromatic group, a benzyl group, asubstituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; wherein: R³, R⁴, R⁵ and R⁶are independently —H, an aliphatic group, a substituted aliphatic group,an aromatic group, a substituted aromatic group, a benzyl group, asubstituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; or R¹ and R², R³ and R⁴, orR⁵ and R⁶ taken together with the atom to which they are bonded, form asubstituted or unsubstituted non-aromatic heterocyclic ring; said acylgroup is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl oraromatic sulfonyl; and R⁴⁰ is —OH, halogen, aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromaticgroup), —O-(substituted aromatic group), an electron withdrawing group,—(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)—O—R²⁰; wherein: u is zero or one; t is aninteger from zero to three; R²⁰, R²¹ or R²² are independently —H, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group or a non-aromatic heterocyclic group; or R²¹and R²², taken together with the nitrogen atom to which they are bonded,form a non-aromatic heterocyclic ring; with the proviso that when R¹ is—H, R² is not methyl.
 43. A method of treating a disease associated withaberrant leukocyte recruitment and/or activation mediated by chemokinereceptor function, said disease being selected from the group consistingof arthritis, psoriasis, multiple sclerosis, rejection of a transplantedorgan or tissue, graft versus host disease, ulcerative colitis, Crohn'sdisease, allergy, asthma, AIDS associated encephalitis, AIDS relatedmaculopapular skin eruption, AIDS related interstitial pneumonia, AIDSrelated enteropathy, AIDS related periportal hepatic inflammation andAIDS related glomerulonephritis, comprising administering to a subjectin need thereof an effective amount of a compound represented by thefollowing structural formula:

or physiologically acceptable salt thereof, wherein: Ar¹ is asubstituted or unsubstituted pyridyl group; Ar² is a substituted orunsubstituted aromatic carbocyclic group; n is an integer from one tofour; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group, —O-(aliphaticgroup), —O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —CN, —COOH, —CO—NR³R⁴ or —NR³R⁴;R² is —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, an aliphaticgroup, a substituted aliphatic group, an aromatic group, a substitutedaromatic group, a benzyl group, a substituted benzyl group, anon-aromatic heterocyclic group or a substituted non-aromaticheterocyclic group; wherein: said acyl group is an aliphatic carbonyl,aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl; and R³, R⁴,R⁵ and R⁶ are independently —H, an aliphatic group, a substitutedaliphatic group, an aromatic group, a substituted aromatic group, abenzyl group, a substituted benzyl group, a non-aromatic heterocyclicgroup or a substituted non-aromatic heterocyclic group; or R¹ and R², R³and R⁴, or R⁵ and R⁶ taken together with the atom to which they arebonded, form a substituted or unsubstituted non-aromatic heterocyclicring; with the proviso that when R¹ is —H, R² is not methyl.
 44. Acompound represented by the following structural formula:

or physiologically acceptable salt thereof, wherein: n is an integerfrom one to four; M is >CR¹R²; R¹ is —H, —OH, an aliphatic group,—O-(aliphatic group), —O-(substituted aliphatic group), —SH,—S-(aliphatic group), —S-(substituted aliphatic group),—OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —CN,—COOH, —CO—NR³R⁴ or —NR³R⁴; and R² is —OH, an acyl group, a substitutedacyl group, —NR⁵R⁶, an aliphatic group, a substituted aliphatic group,an aromatic group, a substituted aromatic group, a benzyl group, asubstituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group; wherein: said acyl group isan aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromaticsulfonyl; R³, R⁴, R⁵ and R⁶ are independently —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup, a benzyl group, a substituted benzyl group, a non-aromaticheterocyclic group or a substituted non-aromatic heterocyclic group; orR¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to whichthey are bonded, form a substituted or unsubstituted non-aromaticheterocyclic ring; R⁴⁰ is —(O)_(u)—(CH₂)_(t)—COOR²⁰; wherein: u is zero;t is zero; and R²⁰ is —H; with the proviso that when R¹ is —H, R² is notmethyl.